Alzheimer's disease (AD) and atherosclerosis share common risk factors. Epidemiological and clinical studies have suggested that vascular risk factors might be important in both diseases. Notably, recent genetic data demonstrated that carders of a common genetic variant (R219K) of ATP-binding cassette transporter A1 (ABCA1), initially linked to a decreased severity of atherosclerosis, have delayed age at onset of Alzheimer's disease. ABCA1 is a major regulator of cholesterol homeostasis. Mutations in the ABCA1 gene cause severe HDL deficiencies characterized by accumulation of cholesterol in cells and prevalent atherosclerosis. The transcriptional upregulation of ABCA1 is controlled by nuclear receptors LXR and PPARgamma - shown to increase HDL levels and decrease atherosclerotic lesions in vivo. Recently, others and we demonstrated that ligands for LXRs increased ABCA1 expression in neuronal cells and reduced amyloid beta (ABeta) secretion. Thus, transcriptional upregulation of ABCA1 triggered by pharmacological activation of LXRs and PPARgamma may decrease amyloid production and plaque formation in the brain. Our proposal has two principal objectives: Aim 1. To determine the effect of synthetic LXR and PPARgamma ligands on ABCA1 expression and APP processing in vitro. We will screen a number of synthetic LXR ligands and PPARgamma agonists for their inhibitory potential on ABeta production in vitro. The effect will be determined in a neuronal cell line and primary neurons. Aim 2. To validate ABCA1 as a therapeutic target by comparing AD-phenotype in APP23/ABCA1 wt and APP23/ABCA1-/- and by further treatments of these mice with LXR and PPARgamma ligands. This Aim has two main objectives: 1). To determine if the targeted disruption of ABCA1 influences APP23 phenotype in APP23/ABCA1-/- in comparison to APP23/ABCA1/wt mice, and 2). To examine ff LXR and PPARgamma ligands exert their effect on ABeta secretion/deposition through ABCAl-dependent mechanism. We will compare the effect of LXR and PPARgamma agonists on AD-like pathology in APP23 mice with either wild type or disrupted ABCA1 gene. We will use two age groups: younger animals to examine the effect exclusively on ABeta production and older mice to answer the question if treatment affects amyloid deposition. The results of our study will advance the understanding how the genes that control intracellular cholesterol content and its redistribution in the brain, influence APP processing and ABeta deposition. The possibility to upregulate ABCA1 by LXR/PPARgamma agonists will establish the pharmacological intervention aiming at ABCA1 as a valuable approach in the drug development and discovery of new therapeutic agents for prevention and/or slowing the progression of Alzheimer's disease.